Tachykinins are a family of peptides which share the common amidated carboxy terminal sequence, EQU Phe--Xaa--Gly--Leu--Met--NH.sub.2
hereinafter referred to as SEQ ID NO:1. Substance P was the first peptide of this family to be isolated, although its purification and the determination of its primary sequence did not occur until the early 1970's. Substance P has the following amino acid sequence, EQU Arg--Pro--Lys--Pro--Gln--Gln--Phe--Phe--Gly--Leu--Met--NH.sub.2
hereinafter referred to as SEQ ID NO:2.
Between 1983 and 1984 several groups reported the isolation of two novel mammalian tachykinins, now termed neurokinin A (also known as substance K, neuromedin L, and neurokinin .alpha.), and neurokinin B (also known as neuromedin K and neurokinin .beta.). See, J. E. Maggio, Peptides, 6 (Supplement 3):237-243 (1985) for a review of these discoveries. Neurokinin A has the following amino acid sequence, EQU His--Lys--Thr--Asp--Ser--Phe--Val--Gly--Leu--Met--NH.sub.2
hereinafter referred to as SEQ ID NO:3. The structure of neurokinin B is the amino acid sequence, EQU Asp--Met--His--Asp--Phe--Phe--Val--Gly--Leu--Met--NH.sub.2
hereinafter referred to as SEQ ID NO:4.
Tachykinins are widely distributed in both the central and peripheral nervous systems, are released from nerves, and exert a variety of biological actions, which, in most cases, depend upon activation of specific receptors expressed on the membrane of target cells.
The mammalian tachykinins substance P, neurokinin A, and neurokinin B act through three major receptor subtypes, denoted as NK-1, NK-2, and NK-3, respectively. These receptors are present in a variety of organs.
Substance P is believed inter alia to be involved in the neurotransmission of pain sensations, specifically in the pain associated with migraine headaches and with arthritis. These peptides have also been implicated in gastrointestinal disorders and diseases of the gastrointestinal tract such as inflammatory bowel disease. Tachykinins have also been implicated as playing a role in numerous other maladies, as discussed infra.
In view of the wide number of clinical maladies associated with an excess of tachykinins, the development of tachykinin receptor antagonists will serve to control these clinical conditions. The earliest tachykinin receptor antagonists were peptide derivatives. These antagonists proved to be of limited pharmaceutical utility because of their metabolic instability.
Recent publications have described novel classes of non-peptidyl tachykinin receptor antagonists which generally have greater oral bioavailability and metabolic stability than the earlier classes of tachykinin receptor antagonists. Examples of such newer non-peptidyl tachykinin receptor antagonists are found in U.S. Pat. No. 5,328,927, issued Jul. 12, 1994; U.S. Pat. No. 5,360,820, issued Nov. 1, 1994; U.S. Pat. No. 5,344,830, issued Sep. 6, 1994; U.S. Pat. No. 5,331,089, issued Jul. 19, 1994; European Patent Publication 591,040 A1, published Apr. 6, 1994; Patent Cooperation Treaty publication WO 94/01402, published Jan. 20, 1994; Patent Cooperation Treaty publication WO 94/04494, published Mar. 3, 1994; and Patent Cooperation Treaty publication WO 93/011609, published Jan. 21, 1993.
In essence, this invention provides a class of potent non-peptide tachykinin receptor antagonists. By virtue of their non-peptide nature, the compounds of the present invention do not suffer from the shortcomings, in terms of metabolic instability, of known peptide-based tachykinin receptor antagonists.
As noted in Patent Cooperation Treaty published application WO 93/01169, published Jan. 21, 1993, compounds similar to those of the present invention have been described in various sources.
Inhibition of benzodiazepine receptor binding in vitro by benzyl (3-(3-indolyl)-2-aminopropionate is disclosed in Biochemical Pharmacology, 30:3016-3019 (1981). Arzneim-Forsch, 32(I):684-685 (1982) reports that benzyl (2-(3-indolyl)-2-aminopropionate is an antisickling agent and an inhibitor of glucose transport in human erythrocytes in vitro. A weak inhibition of estrogen binding to rat alpha-fetoprotein by benzyl 3-(3-indolyl)-2-aminopropionate in vitro is disclosed in journal of Steroid Biochemistry, 16:503-507 (1982).
Australian Journal of Chemistry, 28:2065-2068, discloses 4-nitrobenzyl 3-(3-indolyl)-2-aminopropionate, 4-nitrobenzyl 2-(1,1-dimethylethoxycarbonylamino)-3-(3-indolyl)propionate, and benzyl 2-(1,1-dimethylethoxycarbonylamino)-3-(3-indolyl)propionate. There is no suggestion in this article that the disclosed compounds are useful in medicine.
Journal of Organic Chemistry, 42:1286-1290 (1977), discloses 4-methoxybenzyl 2-(1,1-dimethylethoxycarbonylamino)-3-(3-indolyl)propionat e. No medical use is suggested.
Australian Journal of Chemistry, 31:1865-1868 (1978), discloses 2,4,6-trimethylbenzyl 3-(3-indolyl)-2-aminopropionate and 4-nitrobenzyl 3-phenyl-2-aminopropionate. There is no disclosure of a use in medicine.
There is no suggestion in any of these references of the compounds of the present invention nor their usefulness in treating or preventing conditions associated with an excess of tachykinins.